Comparative profiling of the immune response following grafting in the CNS
Cell therapy for Parkinson’s disease remains one of the most highly anticipated applications for stem cells in the brain repair field. Clinical trials with fetal tissue have provided proof of principle that new dopamine neurons implanted into the brain of Parkinson’s disease patients can provide sustained improvement in motor function. However, the primary source of tissue to be used dopaminergic neurons (DA) cell replacement has not yet been fully determined for a variety of reasons, including ethical considerations surrounding the acquisition of embryonic or fetal stem cells. Despite the so-called ‘immuno-privileged’ environment offered by the brain, extensive work using fetal tissue in animal models and in studies utilizing human tissue it has been shown that while cells transplanted into the brain can survive long-term without immunosuppressive treatment, a long-lasting inflammatory response is present and ultimately compromises the grafted cells. Furthermore, in clinical trials, patients undergoing different immunosuppressive regimes suggest that the host immune response may well have a decisive impact on graft survival and function. Our understanding of the complex interaction between the immune system and the CNS has significantly improved in the recent past and it has become clear that our immune system is intimately involved in CNS damage/repair and disease progression and presumably etiology. Consequently, we propose to assess how dominant adaptive immune factors mediate graft survival, but also determine how these may affect finer aspects of graft function under circumstances of immune limitation, which may occur with advanced CNS disease, extreme youth, or advanced age. Our ability to manipulate cytotoxic T cells and their function allows us to systematically determine the contribution of dominant effectors of systemic graft rejection in the successful engraftment and functioning of transplanted CNS cells. Secondary to this, we will also probe the possibility that other immune factors, including non-cytotoxic and non-ab T cells, pro- and anti-inflammatory cytokines, and innate immune cells and molecules, may modify graft-modulating ability of cytotoxic T cells. Coupled together, we have the unique ability to examine the integrity and function of transplanted cells in an animal model for Parkinson’s Disease (PD) and subsequently define the role of specific immune cells at various stages of appropriate engraftment and functional recovery.
Our propose study will directly and systematically address the immunologic limitations of allogeneic stem cell grafts and begin to elucidate the specific immune cells that influence appropriate engraftment. Furthermore, our proposal will examine the potential of modified immunotherapy in the promotion of successful transplantation for cell replacement therapy in the CNS.
The propose research will directly examine the potential of stem cells to become dopaminergic neurons, survive and establish appropriate connections in the brain for functional recovery in an animal model for Parkinson's disease. These neurons are the same neurons that are damaged in Parkinson’s disease. Furthermore, we will directly examine the role of T cells or immune cells in graft rejection and acceptance. The results to be obtained from this study will provide critical information regarding the role of host immunity in cell replacement therapy for Parkinson’s disease. Therefore, providing the State of California the platform to directly translate what has been learned from this study to the clinic. California has the unique advantage to examine the potential of embryonic derived stem cells as the citizens of this state have invested valuable resources to study and determine the utility of these cells for treating patients with various diseases.